Cisapride, the full chemical name of which is cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidi nyl]-2-methoxy-benzamide, and the chemical structural formula of which is: ##STR1## is a known compound, the preparation and properties of which are described in Canadian Patent 1,183,847 Van Daele, issued Mar. 12, 1985. It is also the subject of Entry No. 2318 of The Merck Index, 11th Edition. According to the disclosure of Canadian Patent 1,183,847, it has pharmacological properties as a stimulator of motility of the gastrointestinal system, rendering it useful as a peristaltic stimulant in the treatment of disorders associated with the gastrointestinal tract.
Three basic methods for the chemical synthesis of cisapride and related benzamide derivative compounds are described, in greater or lesser detail, in aforementioned Canadian patent 1,183,847. In general terms, these three methods are:
in the first method, reaction of an appropriately substituted piperidine-amine with an appropriately substituted benzoic acid or functional equivalent thereof, to form the amide linkage, thus: ##STR2## in the second method, reaction of a 7-oxo-3-azabicyclo[4,1,0]-heptane with an appropriately substituted benzamide, followed by O-alkylation of the piperidine ring, thus: ##STR3## in the third method, reductive N-alkylation of an appropriate piperidinone with an appropriately substituted benzamide, thus: ##STR4##
In all of these general formulae, L, R' and R each represent one of a wide variety of radicals according to the patent, but in the specific case of cisapride preparation, they represent respectively 3-(4-fluorophenoxy) propyl, methyl and hydrogen or an amino protectant group.
Other syntheses involving the conversion of one member of the class of benzamide derivatives of Canadian patent 1,183,847 to another member of the same class, and syntheses for compounds of the class having groupings different from those of cisapride, are also disclosed in the aforesaid Canadian patent.
These prior art syntheses for cisapride all involve the formation of an amide bond between the piperidine moiety and the benzoic acid derived moiety, with the appropriate substituents on each moiety already in place. The first of these methods is disadvantageous because the 4-aminopiperidine starting material must be produced by a reductive amination which produces a mixture of cis with some trans stereoisomer. Since only the cis isomer is pharmaceutically important, in the pharmaceutically important case of cisapride, the cis isomer must at some stage be separated from the cis-trans mixture. This is inefficient and wasteful of material since several recrystallizations may be required. The second of these methods results in substantial amounts of trans isomer, which is not useful in producing such materials such as cisapride. The third method is not fully detailed in the patent disclosure, and turns out to be impractical on a larger scale.